We recently showed in preclinical models and now in patients in our recent neoadjuvant trial, that antiHER2 drug combinations, such as the monoclonal antibody trastuzumab plus the dual HER1/2 kinase inhibitor lapatinib (LT regimen), more completely inhibit the HER receptor network, and are highly effective, achieving substantially high rates of pathological complete response even without chemotherapy. However, even when HER signaling is completely abrogated, many tumors still acquire resistance. Therefore, it is important to understand resistance mechanisms and to identify well tolerated therapeutic strategies that can overcome or prevent this resistance. In this project we will investigate a novel approach to overcome resistance to HER2-targeted LT therapy based on our laboratory discovery that the mevalonate (MVA) pathway is one of the escape pathways that is activated in LT-resistant breast cancer cells, in which HER2 remains inhibited. In addition to cholesterol biosynthesis, the MVA pathway, via isoprenoid intermediates, can also generate cell proliferative and survival signals. Interestingly, we find that blocking this pathway with relatively nontoxic statins leads to remarkable growth inhibition and death of LT-resistant cells, while parental cells are only modestly affected. We therefore hypothesize that the MVA pathway can function as an escape route in HER2+ breast cancer with intrinsic or acquired resistance to potent antiHER2 treatments, by providing alternative survival and proliferative stimuli to bypass sustained HER2 inhibition. We further hypothesize that targeting the MVA pathway will provide a novel therapeutic strategy to overcome antiHER2 treatment resistance. In Aim 1 we will evaluate the role of the MVA pathway in antiHER2 resistance in our diverse in vitro and in vivo models of resistance to HER2 targeted therapies and will identify predictive biomarkers for response to inhibitors of this pathway. In Aim 2 we will elucidate the molecular mechanisms by which the MVA pathway mediates survival. In Aim 3 we will investigate the predictive value of the MVA pathway for the clinical outcomes in our unique set of tumor specimens from our LT neoadjuvant trials, will assess in the ALTTO trial whether patients taking statins along with antiHER2 treatment have a better outcome, and will conduct a clinical trial to test the efficacy of statin in patients with metastatic disease who are resistant to antiHER2 drug combinations. If this study is successful, targeting the MVA pathway could provide a valuable new therapeutic strategy to overcome antiHER2 treatment resistance.